Submissions for variant NM_001378454.1(ALMS1):c.5374_5375delinsAT (p.Ala1792Ile)

dbSNP: rs1131691296

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000494037	SCV000581806	uncertain significance	not provided	2020-12-01	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Invitae	RCV000554375	SCV000631786	uncertain significance	Alstrom syndrome	2022-10-25	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1793 of the ALMS1 protein (p.Ala1793Ile). This variant is present in population databases (no rsID available, gnomAD 0.6%). This variant has not been reported in the literature in individuals affected with ALMS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 429278). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001201217	SCV001372304	uncertain significance	not specified	2020-06-15	criteria provided, single submitter	clinical testing	Variant summary: ALMS1 c.5371_5372delinsAT (p.Ala1791Ile), also named as c.5377_5378delinsAT (p.Ala1793Ile) results in a non-conservative amino acid change in the encoded protein sequence. One of two in-silico tools predict a benign effect of the variant on protein function. The variant allele was found as a multinucleotide variant (2-73679028-GC-AT) at a frequency of 6.4e-05 in 280570 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ALMS1 causing Alstrom Syndrome (6.4e-05 vs 0.0014), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.5371_5372delinsAT in individuals affected with Alstrom Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV002350098	SCV002645145	likely benign	Cardiovascular phenotype	2023-04-17	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Fulgent Genetics, Fulgent Genetics	RCV000554375	SCV002790642	uncertain significance	Alstrom syndrome	2022-01-12	criteria provided, single submitter	clinical testing